The reparative phenomena that follow tissue injury occur within an environment that is different from other extracellular body compartments. Among other characteristics, the wound milieu is defined by a free arginine concentration that is markedly lower than that of plasma. This reduction in extracellular arginine, unique among the amino acids, results primarily from the catabolism of this amino acid by macrophages at the site of injury. Recent findings have demonstrated that altered arginine availability can profoundly modify the metabolism and function of cells that are important to the process of wound healing. Culture of wound macrophages in arginine deficient media results in increased superoxide (O2-) production and phagocytosis. Studies using peritoneal macrophages demonstrated enhanced O2- production, phagocytosis, protein synthesis, lactate production and tumoricidal activity during culture in conditions of reduced arginine availability. Thus, macrophages in wounds not only determine the prevailing extracellular arginine concentration, but may, through the modulation of arginine availability, auto-regulate their state of activation and function. It is also known that products formed during the catabolism of arginine can induce metabolic alterations (inhibition of respiration and DNA synthesis) in other cells and that cytokines likely to be present within wounds (ie: IL-1, TNF and gamma-IFN) can induce the catabolism of arginine by fibroblasts through pathways shown to result in metabolic inhibition. In addition, lymphocyte proliferation is suppressed in arginine- deficient cultures. Thus, arginine may participate in the regulation of the metabolism and function of cellular populations important in wound healing by virtue of: 1) alterations in its availability, 2) effects of the by-products of its metabolism and 3) interactions between arginine or its metabolites with cytokines present within the wound. The objective of the studies in this proposal is to investigate the role of these potential mechanisms in the regulation of cellular metabolism and function in inflammatory cells. These studies will be performed in cultured cells obtained from subcutaneously implanted polyvinyl alcohol sponges in the rat. Elucidation of the role of arginine in the regulation of wound cell function may provide a better understanding of the overall process of inflammation and repair.